Barry J. Hoffer, M.D., Ph. D.

@article{Baratz2011,

title = {Tumor necrosis factor-alpha synthesis inhibitor, 3,6'-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice.},

author = {Renana Baratz and David Tweedie and Vardit Rubovitch and Weiming Luo and Jeong Seon Yoon and Barry J Hoffer and Nigel H Greig and Chaim G Pick},

url = {https://www.ncbi.nlm.nih.gov/pubmed/21740439},

doi = {10.1111/j.1471-4159.2011.07377.x},

issn = {1471-4159 (Electronic); 0022-3042 (Linking)},

year  = {2011},

date = {2011-09-01},

journal = {J Neurochem},

volume = {118},

number = {6},

pages = {1032--1042},

address = {Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.},

abstract = {Mild traumatic brain injury (mTBI) patients do not show clear structural brain defects and, in general, do not require hospitalization, but frequently suffer from long-lasting cognitive, behavioral and emotional difficulties. Although there is no current effective treatment or cure for mTBI, tumor necrosis factor-alpha (TNF-alpha), a cytokine fundamental in the systemic inflammatory process, represents a potential drug target. TNF-alpha levels increase after mTBI and may induce or exacerbate secondary damage to brain tissue. The present study evaluated the efficacy of the experimental TNF-alpha synthesis inhibitor, 3,6'-dithiothalidomide, on recovery of mice from mTBI in a closed head weight-drop model that induces an acute elevation in brain TNF-alpha and an impairment in cognitive performance, as assessed by the Y-maze, by novel object recognition and by passive avoidance paradigms at 72 h and 7 days after injury. These impairments were fully ameliorated in mice that received a one time administration of 3,6'-dithiothalidomide at either a low (28 mg/kg) or high (56 mg/kg) dose provided either 1 h prior to injury, or at 1 or 12 h post-injury. Together, these results implicate TNF-alpha as a drug target for mTBI and suggests that 3,6'-dithiothalidomide may act as a neuroprotective drug to minimize impairment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Good2011,

title = {Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease.},

author = {Cameron H Good and Alexander F Hoffman and Barry J Hoffer and Vladimir I Chefer and Toni S Shippenberg and Cristina M Backman and Nils-Goran Larsson and Lars Olson and Sandra Gellhaar and Dagmar Galter and Carl R Lupica},

url = {https://www.ncbi.nlm.nih.gov/pubmed/21233488},

doi = {10.1096/fj.10-173625},

issn = {1530-6860 (Electronic); 0892-6638 (Linking)},

year  = {2011},

date = {2011-04-01},

journal = {FASEB J},

volume = {25},

number = {4},

pages = {1333--1344},

address = {Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, U.S. Department of Health and Human Services, Baltimore, MD 21224, USA.},

abstract = {Parkinson's disease (PD) involves progressive loss of nigrostriatal dopamine (DA) neurons over an extended period of time. Mitochondrial damage may lead to PD, and neurotoxins affecting mitochondria are widely used to produce degeneration of the nigrostriatal circuitry. Deletion of the mitochondrial transcription factor A gene (Tfam) in C57BL6 mouse DA neurons leads to a slowly progressing parkinsonian phenotype in which motor impairment is first observed at ~12 wk of age. L-DOPA treatment improves motor dysfunction in these "MitoPark" mice, but this declines when DA neuron loss is more complete. To investigate early neurobiological events potentially contributing to PD, we compared the neurochemical and electrophysiological properties of the nigrostriatal circuit in behaviorally asymptomatic 6- to 8-wk-old MitoPark mice and age-matched control littermates. Release, but not uptake of DA, was impaired in MitoPark mouse striatal brain slices, and nigral DA neurons lacked characteristic pacemaker activity compared with control mice. Also, hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel function was reduced in MitoPark DA neurons, although HCN messenger RNA was unchanged. This study demonstrates altered nigrostriatal function that precedes behavioral parkinsonian symptoms in this genetic PD model. A full understanding of these presymptomatic cellular properties may lead to more effective early treatments of PD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Chou2011,

title = {Enhanced survival of dopaminergic neuronal transplants in hemiparkinsonian rats by the p53 inactivator PFT-alpha.},

author = {J Chou and N H Greig and D Reiner and B J Hoffer and Y Wang},

url = {https://www.ncbi.nlm.nih.gov/pubmed/21294958},

doi = {10.3727/096368910X557173},

issn = {1555-3892 (Electronic); 0963-6897 (Linking)},

year  = {2011},

date = {2011-02-08},

journal = {Cell Transplant},

volume = {20},

number = {9},

pages = {1351--1359},

address = {National Institute on Drug Abuse, Baltimore, MD 21224, USA.},

abstract = {A key limiting factor impacting the success of cell transplantation for Parkinson's disease is the survival of the grafted cells, which are often short lived. The focus of this study was to examine a novel strategy to optimize the survival of exogenous fetal ventromesencephalic (VM) grafts by treatment with the p53 inhibitor, pifithrin-alpha (PFT-alpha), to improve the biological outcome of parkinsonian animals. Adult male Sprague-Dawley rats were given 6-hydroxydopamine into the left medial forebrain bundle to induce a hemiparkinsonian state. At 7 weeks after lesioning, animals were grafted with fetal VM or cortical tissue into the lesioned striatum and, thereafter, received daily PFT-alpha or vehicle injections for 5 days. Apomorphine-induced rotational behavior was examined at 2, 6, 9, and 12 weeks after grafting. Analysis of TUNEL or tyrosine hydroxylase (TH) immunostaining was undertaken at 5 days or 4 months after grafting. The transplantation of fetal VM tissue into the lesioned striatum reduced rotational behavior. A further reduction in rotation was apparent in animals receiving PFT-alpha and VM transplants. By contrast, no significant reduction in rotation was evident in animals receiving cortical grafts or cortical grafts + PFT-alpha. PFT-alpha treatment reduced TUNEL labeling and increased TH(+) cell and fiber density in the VM transplants. In conclusion, our data indicate that early postgrafting treatment with PFT-alpha enhances the survival of dopamine cell transplants and augments behavioral recovery in parkinsonian animals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ross2010,

title = {High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio.},

author = {Jaime M Ross and Johanna Oberg and Stefan Brene and Giuseppe Coppotelli and Mugen Terzioglu and Karin Pernold and Michel Goiny and Rouslan Sitnikov and Jan Kehr and Aleksandra Trifunovic and Nils-Goran Larsson and Barry J Hoffer and Lars Olson},

url = {https://www.ncbi.nlm.nih.gov/pubmed/21041631},

doi = {10.1073/pnas.1008189107},

issn = {1091-6490 (Electronic); 0027-8424 (Linking)},

year  = {2010},

date = {2010-11-16},

journal = {Proc Natl Acad Sci U S A},

volume = {107},

number = {46},

pages = {20087--20092},

address = {Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden. rossja@nida.nih.gov},

abstract = {At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate --> lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Airavaara2010,

title = {Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury.},

author = {Mikko Airavaara and Matt J Chiocco and Doug B Howard and Katie L Zuchowski and Johan Peranen and Chao Liu and Shengyun Fang and Barry J Hoffer and Yun Wang and Brandon K Harvey},

url = {https://www.ncbi.nlm.nih.gov/pubmed/20685313},

doi = {10.1016/j.expneurol.2010.05.020},

issn = {1090-2430 (Electronic); 0014-4886 (Linking)},

year  = {2010},

date = {2010-09-01},

journal = {Exp Neurol},

volume = {225},

number = {1},

pages = {104--113},

address = {Neural Protection and Regeneration Section, National Institute on Drug Abuse, IRP, NIH, Baltimore, MD 21201, USA.},

abstract = {Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a secreted protein which reduces endoplasmic reticulum (ER) stress and has neurotrophic effects on dopaminergic neurons. Intracortical delivery of recombinant MANF protein protects tissue from ischemic brain injury in vivo. In this study, we examined the protective effect of adeno-associated virus serotype 7 encoding MANF in a rodent model of stroke. An AAV vector containing human MANF cDNA (AAV-MANF) was constructed and verified for expression of MANF protein. AAV-MANF or an AAV control vector was administered into three sites in the cerebral cortex of adult rats. One week after the vector injections, the right middle cerebral artery (MCA) was ligated for 60min. Behavioral monitoring was conducted using body asymmetry analysis, neurological testing, and locomotor activity. Standard immunohistochemical and western blotting procedures were conducted to study MANF expression. Our data showed that AAV-induced MANF expression is redistributed in neurons and glia in cerebral cortex after ischemia. Pretreatment with AAV-MANF reduced the volume of cerebral infarction and facilitated behavioral recovery in stroke rats. In conclusion, our data suggest that intracortical delivery of AAV-MANF increases MANF protein production and reduces ischemic brain injury. Ischemia also caused redistribution of AAV-mediated MANF protein suggesting an injury-induced release.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}